Webinar presentation magnuson

www.thebeverageinstitute.org

Sponsored by The Beverage Institute for Health & Wellness of The Cola-Cola Company

December 4, 2007

Straight Facts About Low-Calorie Sweeteners

*The opinions expressed by the speakers are their own and donot necessarily reflect the positions or opinions of The Coca-Cola Company.

Straight Facts About Aspartame

& Other Low-Calorie SweetenersDr. George L. Blackburn, MD, PhDDr Blackburn is the S. Daniel Abraham

Associate Professor of Nutrition and

Associate Director of the Division of

Nutrition at Harvard Medical School.

He also serves as Chief of the

Nutrition/Metabolism Laboratory and

Director of the Center for the Study of

Nutrition Medicine, affiliated with the

Beth Israel Deaconess Medical Center in

Boston. He is an honorary member of

the American Dietetic Association and an

American Society for Nutrition Fellow.

Dr. Bernadene Magnuson, PhDDr. Magnuson is Assistant Professor of

Nutrition and Food Science at the

University of Maryland, where she

conducts research on food toxicology,

diet and cancer prevention and teaches

food science and food toxicology. She

was the lead author of a recent expert

review of the safety of aspartame

published in the September 2007 issue of

Critical Reviews of Toxicology.

Obesity Expert George L. Blackburn, MD, PhD*

Toxicologist Bernadene Magnuson, PhD*

Sponsored by The Beverage Institute for Health & Wellnessof The Cola-Cola Company



December 4, 2007


Bernadene Magnuson, PhDDr. Magnuson is Assistant Professor of Nutrition

and Food Science at the University of Maryland,

where she conducts research on food toxicology,

diet and cancer prevention and teaches food

science and food toxicology. She was the lead

author of a recent expert review of the safety of

aspartame published in the September 2007

issue of Critical Reviews of Toxicology.

Expert Review of The Safety ofAspartame



December 4, 2007


Bernadene Magnuson, Ph.D.

Expert Panel

William J. Waddell, M.D., Chair

John Doull, M.D., Ph.D.

Robert Kroes, Ph.D., DVM

Gary M. Marsh, Ph.D., F.A.C.E.

Michael W. Pariza, Ph.D.

Peter S. Spencer, Ph.D., FRCPath

Ron Walker, Ph.D.

Gary M. Williams, M.D.

Critical Reviews in Toxicology, 2007; 37:629–727.

Expert Review of the Safety ofAspartame



December 4, 2007


Low-Calorie Sweeteners

• Questions regarding the safety of

aspartame have continued to surface in the

press and internet

• Recent lifetime exposure studies also brought

aspartame safety into question

• Goal = convene an independent international

panel of toxicology experts to review all

scientific studies and assess the safety of

current consumption of aspartame



December 4, 2007


Aspartame

http://www.3dchem.com/

Background



December 4, 2007


Aspartame Stability

Not Sweet

• Can breakdown– with long term storage

– conditions high temperature and high pH

• Breakdown products– Aspartylphenylalanine (dipeptide)

– Diketopiperazine (DKP) (cyclic dipeptide)

– Methanol

– Aspartate and phenylalanine

• Breakdown product safety also evaluated



December 4, 2007


Premarket Safety Evaluation

• To support aspartame safety, comprehensivebattery of studies were conducted– Acute, Sub-chronic, Long-term toxicity

– Carcinogenicity

– Genetic toxicity

– Reproductive toxicity

– Teratogenicity

– Also human studies – blood chemistry, diabetics,children

• Data reviewed by every major internationalfood authority (FDA, Health Canada, EU,JECFA, etc.)

• Approved in over 130 countries

Aspartame:Background



December 4, 2007


Aspartame ADI Values

• Acceptable Daily Intake (ADI) = amount considered safe toconsume every day for a life time without adverse effects

– DOES NOT mean that consumption greater than ADI willhave any effect because of conservative nature

• ADI is set by

– determining the amount animals can consume every daywithout effect = No-Observed Effect Level (NOEL)

– Then apply “safety factors” to account for

• differences between individuals (10 X)

• differences between humans and animals (10 X)

• NOEL/safety factors = ADI

• FDA has set the ADI at 50 mg/kg body wt




December 4, 2007


3297Tabletop sweetener (packet)

1442Gelatin (4 oz.)

1133Powdered soft drink (8 oz.)

620Carbonated soft drink (12 oz.)

Child(50 lb.)

Adult(150 lb.)

Food/Beverage

Number of Servings/day to reach ADI (50 mg/kg body weight)




December 4, 2007


Applications/Use of Aspartame

• Carbonated soft drinks

• Juices

• Puddings, fillings, jellies

• Desserts and toppings

• Table-top sweeteners(tablets and powders)

• Chewing gum

• Fruit preserves

• Bread spreads

• Frozen desserts

• Dairy products

• Jams, marmalades

• Breakfast cereals

• Confectionery

• Hot chocolate drinks

• Multivitamins

• Micro breath mints

• Personal care products,pharmaceuticals




December 4, 2007


The Process-Literature

• Scientific literature databases

• FDA Federal Register

• Unpublished regulatory submission reports

• National Toxicology Program studies

• Selection of studies

– Over 500 articles cited in this report

– Elimination criteria

• Research on sensory and/or product applications

• Investigating potential health benefit

Expert Panel:The Process



December 4, 2007


• Analysis of current consumption of aspartame

– Proprietary method of analysis (Burdock Group)

– Food intakes from National Health and Nutrition

Examination Survey (NHANES) 2001-2002, USDA.

– Levels of aspartame content in foods

• Typical use levels from industry

• Levels reported in literature

• Assumptions included all artificial sweetener were

aspartame, highest level reported used as default

The Process - Consumption

Expert Panel:The Process



December 4, 2007


Values for users only mg/kg bw/day

50th Percentile (Mean) 4.8

90th Percentile 10.4

95th Percentile 13.3

Acceptable Daily Intake = 50 mg/kg bw/d

ADI level = considered safe to consume every day for life

NHANES-Based Estimate ofAspartame Consumption

Expert Panel:The Findings



December 4, 2007


• The intake of aspartame has increased in

recent years; the change is not dramatic

• Remains well below the ADI even for high

intake subpopulations

• NHANES over-estimation; assumptions

• Worst-case scenario predictions suggest

chronic intakes will not reach the ADI

Consumption of Aspartame




December 4, 2007


Intestinal Lumen Mucosa Cell

Methanol

Aspartate

Phenylalanine

Aspartame

Portal Blood

Aspartame

Esterases

Methanol (10%)

Asp/Phe

Aspartate (40%)

Phenylalanine (50%)

Peptidases

+

Dipeptide Transport

System

Aspartame

Esterases

Methanol

Asp/Phe

Aspartate

Phenylalanine

Peptidases

+

+

Aspartame Absorption in the Gut




December 4, 2007


12 oz diet beveragewith aspartame

90 72 18

12 oz milk 606 888 -

Medium banana 58 146 21

12 oz orange juice 36 276 23

12 oz tomato juice 58 346 107

Phenylalanine* Aspartic

Acid*

Methanol

Phenylalanine, Aspartic Acid &Methanol Content of Foods


*amino acids



December 4, 2007


Methanol Metabolism

Methanol

Ch3OH

Formaldehyde

HCHO-

Formic acid

HCOO-

CO2 + H20

Purine synthesis

Excreted

in Urine

Amino Acids

Nucleic Acids




December 4, 2007


Methanol

FormaldehydeT = 1.5 min

Formic acid T = 3-6 hr

CO2 + H20

Lowest blood level associated with toxicity = 126 mg/dL Safe dose = 2 gm for adult

Conversion very rapid:No accumulation

Accumulation of formic acid= toxicity of methanol

Normal range in blood= 7- 63 mg/L

Alcohol dehydrogenase in liver

Kostic and Dart, 2003

Methanol Metabolism




December 4, 2007


• Constituent of many foods

• Produced during the endogenous demethylation of foods

and drugs, such as caffeine

– One cup of coffee produces 30 mg of formaldehyde

• Essential in one-carbon pool metabolism.

– Formic acid is a substrate for nucleotide synthesis

• Calculated >50,000 mg formaldehyde is produced and

metabolized daily in an adult human body

• Adult human liver will metabolize 22 mg formaldehyde

per minute to formic acid and CO2 and water

Clary and Sullivan, 1999

Formaldehyde Metabolism




December 4, 2007


No change in blood methanol or formicacid levels

600 mg per hr for8 hr

Healthy adults

methanol < LOD

methanol < LOD

methanol peak = 1.02 at 90 min, then~0.45 at 2.5 hr

34 mg/kg; n=10

50 mg/kg; n=6

100 mg/kg; n=8

Healthy Infants

methanol < LOD*

methanol peak 1.27, <LOD at 8 hr



No change in blood formic acid

34 mg/kg; n=12

100 mg/kg; n=6

150 mg/kg; n=6

200 mg/kg; n=6

Health adults

Methanol and formic acid (mg/dL)Dose (mg/kg): NSubjects

Effect of Aspartame on BloodMethanol & Formic Acid

Lowest blood level ~ toxicity = 126.0 mg/dL*LOD= limit of detection, 0.35 mg/dL

Stegink et al., 1981, 1983, 1989




December 4, 2007


• Acute toxicity

• Subacute toxicity

• Chronic bioassays

• Neurotoxicity

• Teratogenesis

• Reproductive toxicity

• Genotoxicity

• Immunotoxicity

• Cytotoxicity

• Bacterial studies

• Human clinical studies

– Blood chemistry, body wt

– Methanol, formaldehyde

– Headaches

– Behavior and cognitivefunction

– Induction of seizures

• Epidemiological studies

Safety Evaluations of Aspartame

Panel Findings:Toxicity Studies



December 4, 2007


• 5 with rats, doses up to 5000 mg/kg/d

• 3 with mice, doses up to 4000 mg/kg/d

• 3 with transgenic high cancer risk mice at

doses up to 7500 mg/kg/d

• 1 with hamsters, doses up to 12,000 mg/kg

• 1 with dogs, doses up to 4000 mg/kg/d

• 2 with rats to assess promotion of existing

cancers

Long Term Animal Studies-Cancer




December 4, 2007


• 14/15 animal studies had negative findings indicatingno evidence of carcinogenic effect or cancerpromoting effect of aspartame

• One study concluded that aspartame has carcinogenicpotential (Ramazzini Foundation)

– This panel agreed with findings of numerous foodauthorities that Ramazzini study:• Numerous methodological and interpretation errors

• Provided “no credible evidence that aspartame iscarcinogenic”

• “Is no need to further review the safety ofaspartame”

• “No need to revise previously established ADI”

Long Term Animal Studies-Cancer




December 4, 2007


• Effect of aspartame studied during

reproduction, pregnancy, lactation and

development in rats, mice, hamsters, rabbits

and humans

• No effect at doses up to 4000 mg/kg/day in

rodents and 1600 mg/kg/day in rabbits

• No change in breast milk composition in

humans at doses up to 50 mg/kg

• Conclusion – no evidence of adverse effects

Studies during Pregnancy andDevelopment

Expert Findings:Toxicity Studies



December 4, 2007


• Have been several, conflicting results with

most showing no effect; however some small

studies suggesting may be a susceptible

subset

• There is no known mechanism

• Is difficult to study - no objective measure,

power of suggestion and inconsistent results

Studies on Headaches




December 4, 2007


• Animal studies

– Up to 4% of diet (4000 mg/kg/d), no effect onneuronal function, learning or behavior despitechanges in blood and brain amino acids levels

• Human studies

– Normal children, hyperactive children, childrenwith PKU, aggressive school boys, sugar-sensitive children, airline pilots

– Healthy adults, adults with Parkinson’s disease,depression

– No effect of aspartame on learning or behaviorin all but 1 study

Neurotoxicity-Learning Behavior




December 4, 2007


• Animals - No effect - doses up to 1000mg/kg/d– Evaluated in a variety of animal models to induce

convulsions and seizures(Pinto and Maher, 1988; Guiso et al., 1988; Cane et al.,1989; Tilson etal., 1989; Helai et al., 1996)

– Genetically epilepsy-prone rats

(Daily et al., 1991)

• Human studies - No significant effect onseizures observed with doses of 34-50 mg/kg– Children diagnosed with petite mal seizures,

individuals with epilepsy, self-reported aspartame-sensitive adults

(Camfield et al., 1992; Shaywitz et al., 1994, Rowan et al., 1995)

Neurotoxicity-Seizures




December 4, 2007

Straight Facts About Low-Calorie Sweeteners Expert Findings:Toxicity Studies

No association between cancer

and sweetener consumptionFood frequencyquestionnaires

Case control study- various

cancer types (n = 8976 cases,

7028 controls)

Gallus

(2007 )

No associations betweenhematopeoitic or brain

cancers and aspartameconsumption

Food frequencyquestionnaires

Prospective study473,984 subjects, 5 yr

Hematopoietic cancers(n=2,106);

Brain cancers (n=376)

Lim(2006)

from NCI

No association betweenconsumption during

pregnancy and risk

Food frequencycompleted by mothers of

children

315 children - braintumor, 315 controls

Bunin(2005)

No associationRecall of low calorie soft

drinks.

30 brain tumor cases 45

controls

Hardell

(2001)

No associationDietary recall - Personalinterview

56 brain tumor cases 94controls

Gurney(1997)

Incidence increased after

aspartame on market

Not measuredUS SEER brain tumor data

from 9 locations

Olney

(1996)

ConclusionsConsumption ofAsp

Type of study (N)Author

Epidemiological Studies



December 4, 2007


• Metabolism is well understood and followsthat of other common foods.

• Consumption, even at levels much higherthan that expected under typicalcircumstances, has virtually no impact onlevels of blood constituents such as aminoacids, methanol or glucose.

• A well-studied sweetener whose safety isclearly documented and well establishedthrough extensive laboratory testing,animal experiments, epidemiologicalstudies and human clinical trials.

Expert Findings:Summary

Aspartame - Summary



December 4, 2007


• No credible link between consumption of

aspartame at levels found in the human

diet and conditions related to the nervous

system and behavior, nor any other

symptom or illness.

• Non-genotoxic and there is no credible

evidence that aspartame is carcinogenic.

• Does not increase hunger in those who

use it; to the contrary, studies indicate it

might be an effective tool as part of an

overall weight management program.

Expert Findings:Summary

Aspartame



December 4, 2007


• Aspartame is a well-characterized,

thoroughly studied, high-intensity

sweetener that has a long history of

safe use in the food supply and can

help reduce the caloric content of a

wide variety of foods.

Critical Reviews in Toxicology, 37:629–727, 2007

Panel Conclusions

Expert Panel:Conclusions



December 4, 2007


*The opinions expressed by the speakers are their own and donot necessarily reflect the positions or opinions of The Coca-Cola Company.

Straight Facts About Aspartame

& Other Low-Calorie SweetenersDr. George L. Blackburn, MD, PhDDr Blackburn is the S. Daniel Abraham

Associate Professor of Nutrition and

Associate Director of the Division of

Nutrition at Harvard Medical School.

He also serves as Chief of the

Nutrition/Metabolism Laboratory and

Director of the Center for the Study of

Nutrition Medicine, affiliated with the

Beth Israel Deaconess Medical Center in

Boston. He is an honorary member of

the American Dietetic Association and an

American Society for Nutrition Fellow.

Dr. Bernadene Magnuson, PhDDr. Magnuson is Assistant Professor of

Nutrition and Food Science at the

University of Maryland, where she

conducts research on food toxicology,

diet and cancer prevention and teaches

food science and food toxicology. She

was the lead author of a recent expert

review of the safety of aspartame

published in the September 2007 issue of

Critical Reviews of Toxicology.

Obesity Expert George L. Blackburn, MD, PhD*

Toxicologist Bernadene Magnuson, PhD*

Sponsored by The Beverage Institute for Health & Wellnessof The Cola-Cola Company

THANK YOU!

Documents

Webinar presentation magnuson